The acyclic sugar alcohol mannitol, shown below, is an excipient commonly used in the pharmaceutical formulation of tablets, granulated powders for oral use, and as a stabilizer in protein formulations. Mannitol is generally described to be non-hygroscopic.

Three polymorphic crystal forms (A. Burger et al. J. Pharm. Sci. 2000, 89, 457) and a hemihydrate (L. Yu et al. Pharm. Sci. 1999, 88, 196) of mannitol are described in the literature. The term “modification” as used herein refers to one of the three polymorphic crystal forms. By “polymorphic” what is meant is that mannitol is known to crystallize into one of at least three different solid-state structures. Each structure exhibits different solid-state properties such as dissolution, hygroscopicity, and compression properties. For example modification I (β-mannitol, I) is the thermodynamically stable crystal form under ambient conditions. Modification II (α-mannitol, II) and modification III (δ-mannitol, III) are thermodynamically metastable under ambient conditions, but can be crystallized in large quantities and are durable. In one report, for example, modification III did not transform into modification I over a period of 5 years if kept dry (A. Burger et al. J. Pharm. Sci. 2000, 89, 457). The physical properties such as melting points, enthalpies of fusion, vibrational spectra and densities are described in the scientific literature (A. Burger et al J. Pharm. Sci 2000, 89, 457). Mannitol hemihydrate was observed during lyophilization of aqueous solutions of mannitol. However, the hemihydrate is unstable under ambient conditions. Single crystal X-ray structures have been reported for modifications I: (a) Berman et at. Acta Cryst. B 1968, 24, 442; b) Walter-Levy C. R. Acad. Sci., Ser. C 1968, 267, 1779; c) Kaminsky et al. Z. Krystallogr. 1997, 212, 283; d) Fronczek et al. Acta Cryst. C 2003, 59, 567), II (a) Walter-Levy C. R. Acad. Sci., Ser. C 1968, 267, 1779; b) Fronczek et al. Acta Cryst. C 2003, 59, 0567), and III (a) Walter-Levy C. R. Acad Sci., Ser. C 1968, 267, 1779; b) Backer Z. Phys. 1923, 14, 369; c) Fronczek et al. Acta Cryst. C 2003, 59, o567). A crystal structure solution from powder was published for the hemihydrate and also for modification III.
One feature of an excipient is its ability to compress during the formation of a tablet. For example, paracetamol (Joiris et al. Pharm. Res. 1998, 15, 1122) exists in multiple crystalline forms including the thermodynamically stable crystal form (monoclinic form) and a metastable form which is orthorhombic. The monoclinic form cannot be compressed directly which is why paracetamol tablets are usually produced through a wet granulation process. The metastable orthorhombic crystal form of paracetamol, however, can be compressed directly without having to go through the additional wet granulation processing required by the monoclinic form. Thus, by avoiding a wet granulation process, the orthorhombic form is less expensive and quicker to process.
Likewise, the compression properties of the crystal forms of mannitol differ from each other (A. Burger et al. J. Pharm. Sci. 2000, 89, 457). The compressibility of a material is its ability to be reduced in volume as a result of an applied pressure. Mannitol modification III exhibits the best compressibility followed by modification I and II (A. Burger et al. J. Pharm. Sci. 2000, 89, 457). Additionally, modification III shows better compactibility and friction of compacts (tablets) when compared with modifications I and II. The compactibility of a material is its ability to produce compacts with sufficient strength (hardness, friability) under the effect of densification. The friction of the compacts is usually determined by measuring the ejection force that is necessary to eject a compact (tablet) out of the tabletting machine as a function of the compression pressure that is needed to form the compact (tablet). Hence, modification III shows the best direct compression properties among the three anhydrous forms (A. Burger et al. J. Pharm. Sci. 2000, 89, 457). Currently, the majority of mannitol produced for pharmaceutical use is the thermodynamically stable modification I. In spray-dried products, mannitol usually exists as mixtures of modifications I and II.
Although the formation of mannitol modification III is known, for commercial production, it occurs as a byproduct of D-sorbitol production, which involves catalytic hydrogenation of glucose and/or fructose. In this commercial process, the mannitol is separated from the D-sorbitol by fractional crystallization. Mannitol modification III results because D-sorbitol inhibits the phase transformation of modification III into a thermodynamically more stable crystal form. The amounts of mannitol modification III produced as a by-product of sorbitol production often contain impurities and the quantities produced are insufficient to meet currently commercial demands. Alternatively, small amounts of mannitol modification III may be made by rapidly cooling an aqueous solution of mannitol to 0° C. and rapidly isolating the resulting solid before modification III reverts to modification I or II (A. Burger et al. J. Pharm. Sci. 2000, 89, 457). This process however, cannot be scaled up to produce commercially useful amounts of mannitol modification III.
Thus, modification III has been produced as a byproduct of sorbitol production but has not been made by direct crystallization methods. It should also be appreciated that the current demand for mannitol modification III is greater than the amount that may be produced by the current commercial method described above.
It would be advantageous, therefore, to have a method for making modification III of mannitol separate from the production of sorbitol. It would also be advantageous if the method could make commercially useful amounts of mannitol modification III.